Advances in the pharmacologic treatment of HIV infection have led to a remarkable reduction in viral load for many HIV-infected individuals. Despite the success of antiviral drugs, a significant percentage of patients remain resistant or intolerant to them, and virus or low level persistent viral replication may continue to damage the immune system. A major challenge in AIDS research is to augment immune function in infected patients and eliminate residual virus in those with ow viral loads. In this project, combination antiviral gene therapy, together with anti- retroviral drugs and immunostimulatory treatments, will be analyzed. The genes transfer approaches are based upon expression of intracellular gene products which inhabit viral replication. We have previously shown that an essential viral protein, Rev M10, prolongs the survival of T cells transduced with non-viral and retroviral vectors in HIV-infected subjects. In this study, Rev M10 will be explored in combination with other anti- retroviral genes which affect virus entry. First, the efficacy of targeting relevant chemokine receptors, or other genes which affect the afferent phase of the virus life cycle, will be compared to Rev M10, alone or in combination. A second aim is to develop improved vector production systems. Such retroviral delivery systems and evolving lentiviral vectors will be adapted for human trials in collaboration with Drs. Kohn (Project 1) and Nolan (Project 3). In collaboration with Project 4, the immunogenicity of these antiviral genes and their effects on immune function in animal models or in human cells be performed, particularly those involving inhibition of chemokine receptor function. Finally, the optimal combination of antiviral genes will be used in clinical studies in HIV-infected subjects, and the engraftment of genetically-modified cells in the presence or absence of anti-retroviral therapy and/or immunostimulation will be explored. These studies will be performed both in adult and pediatric AIDS patients, in collaborations with Drs. Kohn and Wara, in an expansion of previous work supported by SPIRAT. Together, these studies will explore the potential for gene transfer to complement existing antiviral pharmacologic and immune stimulation treatments, to promote immune reconstitution, and provide further information about the effects of these treatments on lymphocyte survival in HIV infection. Development of such combination approaches may ultimately enhance long- term immune function and contribute to elimination of the residually infected cells in patients during treatment of HIV infection.